Transdermal drug delivery offers many advantages over other types of drug delivery. These advantages include improved local, specific drug delivery; avoiding the gastrointestinal complications caused by oral delivery, and improved efficacy and safety profiles for the drugs. While the process of transdermal drug delivery offers these and other advantages, a system that can quickly, precisely and reliably deliver predictable quantities of a wide spectrum of different drug molecules through the skin has is heretofore not been developed.
The evolution of transdermal drug delivery has centered around patch technology. Patch technology is based on the ability to hold an active ingredient in constant contact with the epidermis over substantial periods of time, certain drug molecules, held in such a state, will eventually transfer from the patch into the skin and to a small and variable degree, into the bloodstream. Thus, patch technology relies on the ability of the human body to passively pick up drug molecules through the skin. Transdermal drug delivery using patch technology has recently been applied for delivery of nicotine, in an effort to assist smokers in quitting, the delivery of nitroglycerine to angina sufferers, the delivery of replacement hormones (e.g., estrogen, progesterone and testosterone) and for the delivery of scopolamine for motion sickness. These drug delivery systems comprise a patch with an active ingredient such as a drug incorporated therein, the patch also includes an adhesive for attachment to the skin so as to place the active ingredient in close proximity to the skin.
Problems with patch technology abound. First, most active drug molecules (with the exception of those previously listed) have difficulty passing through the skin, as the skin tissue poses a significant barrier. In fact, in order for a drug molecule to reach the bloodstream, it must pass through the stratum corneum (an especially dense layer of cells), the dermis tissue layer and finally through the wall of the blood vessel. Second, real world conditions such as the patient""s obesity, metabolism and circulatory efficiency can effectively inhibit the efficiency of patch-based transdermal drug delivery. Third, patch technology can be used only for conditions involving long, non-acute treatment periods, since the typical transport rate of drug molecules is typically so slow and variable. Finally, patch adhesion to the skin may cause extensive skin trauma as well as cosmetic problems. Specifically, most adhesives currently used tend to aggressively adhere to the skin in a manner that their removal may cause irritation and trauma. Indeed, subsequent patches used by a given individual are often applied to a different area of the skin in order to minimize such irritation and trauma to the skin.
In an effort to enhance the efficiency of transdermal drug delivery, the prior art teaches that by mixing certain individual ingredients (penetration enhancers) with a drug molecule, the ability of the drug molecule to pass through the skin is increased somewhat. For example, U.S. Pat. No. 4,933,184 discloses the use of menthol as a penetration enhancer; U.S. Pat. No. 5,229,130 discloses the use of vegetable oil (soybean and/or coconut oil) as a penetration enhancer; and U.S. Pat. No. 4,440,777 discloses the use of eucalyptol as a penetration enhancer.
Although mixing a penetration enhancer with a drug molecule helps to somewhat increase the speed and efficiency of drug delivery into the skin, problems are still present. First, the aforementioned penetration enhancers constitute a passive, not an active, transport system. Penetration enhancers may improve the transportation of the drug through the outer layers of skin and into the lower skin tissue but they do not significantly enhance the second stage of transfer through the wall of the blood vessel and into the bloodstream. Second, since penetration enhancers are not chemically linked to the drug molecule, the transport of the penetration enhancer into the skin does not necessarily mean that the drug molecule has penetrated into the skin.
U.S. Pat. Nos. 5,460,821, 5,645,854 and 5,853,751 disclose efficient transdermal drug, delivery systems created by combining penetration enhancers, chemical vasodilators, active drug ingredients and a binding element. These systems function by allowing the penetrating enhancers to pass through the barrier layer of the skin, and in a physically associated complex, bring all the components of the delivery system into the dermal layer of the skin. Once in the dermal layer of the skin, the vasodilators act to expand or dilate the capillaries and other blood vessels in and beneath the dermal layer, resulting in an increase in blood flowing into and away from the site of system application. The purpose of the polymeric binding element is not only to provide a binding agent, but also to function as a delivery vehicle for the transdermal release of the vasodilator and active drug molecule, post stratum corneum penetration.
However, polymeric binding elements have a substantial molecular weight, which may inhibit or retard their ability to penetrate the skin. Secondly, alcohol soluble vasodilators and alcohol soluble active drug molecules can be difficult to associate with some binding elements in a mixture. Finally, as a result of the physical and chemical properties of some polymeric binding elements, they can act as thickening agents in the solution, which may not be desirable in certain applications.
It is therefore an object of the present invention to provide a transdermal drug transport system that efficiently and easily allows for the effective delivery of a broad range of active drug ingredients through the skin and into the blood supply of a living organism, including animals and humans, without the use of a polymeric binding element.
The problems of the prior art have been overcome by the present invention, which provides an efficient, predictable and reliable active ingredient transdermal delivery system for one or more active ingredients. More specifically, the present invention combines functional elements of the transdermal drug delivery system that can perform in more than one functional capacity to achieve the results of delivering a drug or therapeutic or diagnostic agent through the skin and into the bodily fluids. The present invention utilizes the solubility of the active drug molecule and/or the vasodilator and creates a mixture where the active drug molecule is dissolved into a solvent, the vasodilator is dissolved into a solvent which may be the same or different from the solvent used for the active drug molecule, and a penetration enhancer is added to the mixture but is not necessarily bound to either the active ingredient or the vasodilator. The need for a polymeric binding agent is eliminated, thus diminishing the total molecular weight of the mixture and increasing the penetration and delivery efficiency of selected active ingredients, including but not limited to drugs.